This invention relates generally to medical device system for therapy of cardiovascular disorders, more specifically to adjunct (add-on) treatment of certain cardiovascular disorders by neuromodulation of a selected nerve or nerve bundle, utilizing an implanted lead-receiver and an external stimulator.
Electrical stimulation of the vagus nerve, and the profound effects of electrical stimulation of the vagus nerve on the central nervous system (CNS) activity extends back to the 1930""s. Medical research has furthered our understanding of the role of nervous control of body functions. In the human body there are two vagal nerves (VN), the right VN and the left VN. The innervation of the right and left vagus nerves is different. The innervation of the right vagus nerve is predominately to the sinus (SA) node of the heart, and its stimulation results in slowing of the sinus rate. The cardiac innervation of the left vagus nerve is predominately to the AV node, and its stimulation results in delaying the conduction through the atrioventricular (AV) node.
The system and method of the current invention utilizes an implanted lead-receiver, and an external stimulator for adjunct (add-on) treatment or alleviation of symptoms for certain cardiovascular disorders, such as atrial fibrillation, inappropriate sinus tachycardia, and refractory hypertension. The system of this invention delivers neuromodulation pulses according to a limited number of predetermined programs, which are stored in the external stimulator, and can be activated by pressing a button. The predetermined programs contain unique combinations of pulse amplitude, pulse width, frequency of pulses, on-time and off-time. In one embodiment, the system contains a telecommunications module within the external stimulator. In such an embodiment, the external stimulator can be controlled remotely, via wireless communication.
FIGS. 1A and 1B are simplified schematic diagrams showing nervous control of cardiovascular function. As shown in FIG. 1A, The cardiovascular (CV) center 222 located in the medullary center in the brain influences and controls cardiovascular functions such as heart rate, contractactility, and blood vessels. The cardiovascular center 222 in the brain 220, receives input from the higher centers in the brain 224 and from receptors 226 such as baroreceptors and propriocepters. The cardiovascular (CV) center 222 of the brain 220 controls the effector organs in the body by increasing the frequency of nerve impulses. The CV center 222 decreases heart rate by parasympathetic stimulation via efferent impulses carried by the 10th cranial nerve or the vagus nerve. The CV center can also increase heart rate and cause vasoconstriction via sympathetic stimulation. Thus, the CV center 222 in the brain 220 exerts its control via the opposing actions of the sympathetic and parasympathetic stimulation.
Further, as shown in FIG. 1B baroreceptors located in the aortic arch 262, and in the carotid sinus 260 send blood pressure information to the cardiovascular (CV) center 222 located in Medulla Oblongata 240 of the brain 220. This information is carried by afferent fibers of Glossopharyngeal Nerve 55 and Vagus Nerve 54.
Additionally of interest to the current patent application, the efferent fibers of the right vagus nerve predominately innervate the sinus node 252 and stimulation of these fibers will be used to control (slow-down) heart rate for Inappropriate Sinus Tachycardia Syndrome. The efferent fibers from the left vagus nerve predominately innervate the A-V node 256 of heart, and efferent stimulation of the left vagus nerve 54 will be used for controlling heart rate as adjunct (add-on) therapy for atrial fibrillation in this invention.
Atrial fibrillation (AF) is both the most common sustained arrhythmia encountered in clinical practice, and the most common arrhythmia-related cause of hospital admission. Although health utilization costs related to AF are significant, little is known about its incidence and prevalence. Estimates indicate that 2.2 million Americans have AF and that 160,000 new cases are diagnosed each year. The incidence is higher in older adults, whose risk for developing AF is associated with advanced age. During atrial fibrillation, the atria of the heart discharge at a rate between 350 and 600 per minute. The ventricular rate during atrial fibrillation is dependent on the conducting ability of the AV node which is itself influenced by the autonomic system. Atrioventricular conduction will be enhanced by sympathetic nervous system activity and depressed by high vagal tone. In patients with normal atrioventricular conduction, the ventricular rate ranges from 100 to 180 beats per minute.
AF is characterized by a rapid, irregular ventricular rate, the irregularity being in rhythm and arterial pulse pressure amplitude. This can occur to such an extent that multiple pulse deficits (absence of an arterial pulse following ventricular excitation) are present. Current therapies are designed to extinguish the fibrillation activity or to control or abolish atrioventricular (AV) conduction.
Thus, the two components of acute management of patients with atrial fibrillation include control of ventricular rate and conversion to sinus rhythm. The traditional first step in acute treatment of patients with symptomatic AF who have a rapid ventricular response is to slow the ventricular rate. The first line of defense is usually drugs such as Digoxin, Metoprolol, Esmolol and verapamil etc. Drugs typically have side effects, and some patients may be refractory to drugs. Non-pharmacologic adjunct therapy such as nerve stimulation offers an alternative mode of therapy.
In a paper published by Van den Berg et al in the Aug. 19, 1997 issue of Circulation, the authors showed that heart rate variability in patients with atrial fibrillation is related to vagal tone. In an abstract published at the American Heart Association meeting, by Tabata et al from the Cleveland Clinic Foundation, the authors presented the results of heart rate reduction by vagus nerve stimulation on left ventricular systolic function. Their data showed a dramatic decrease in ejection fraction and stroke volume as atrial fibrillation was induced. Then, while still in atrial fibrillation, a return towards baseline of both ejection fraction and stroke volume, with vagus nerve stimulation of the atrio-ventricular (AV) node.
Thus, with the system of the present invention where an implanted lead-receiver is implanted within the body, and a stimulator with predetermined programs is external to the body, would be useful. The implantable and external components are inductively coupled. With turning the stimulator xe2x80x9conxe2x80x9d, the symptoms of atrial fibrillation would be alleviated by decreasing the heart rate and increasing the stroke volume and ejection fraction.
Inappropriate Sinus Tachycardia is a clinical syndrome with a relative or absolute increase of heart rate at rest or an exaggerated heart rate response inappropriate to the degree of physical or emotional stress. On the surface electrocardiogram, P-wave morphology during tachycardia is nearly identical to the P-wave morphology during normal sinus rhythm. The clinical manifestations of this syndrome complex are diverse. Young women make up most of the patient population, and clinical symptoms can range from intermittent palpitations to multiple system complaints.
Clinical signs and symptoms associated with inappropriate sinus tachycardia are often refractory to medical therapy with drugs. Drugs, such as xcex2-adrenergic blockers or calcium channel blockers, usually either are not effective in controlling symptoms or are poorly tolerated. It is hypothesized that the inappropriate sinus tachycardia response in these patients is due to underlying autonomic dysregulation. The electrophysiologic findings are consistent with the diagnosis of inappropriate sinus tachycardia in the following circumstances: Gradual increase (warm-up) and decrease (cool-down) in heart rate during initiation and termination of isoproterenol infusion, consistent with an automatic mechanism of sinus node function; Surface P-wave morphology similar to that observed during sinus rhythm; and Earliest endocardial activation along the crista terminalis estimated from fluoroscopic images. Clinically, Inappropriate Sinus Tachycardia is divided into 2 subsets, a) postural orthostatic tachycardia syndrome (POTS), and b) non-postural orthostatic tachycardia syndrome (non-POTS). The second category, non-POTS would be alleviated by decreasing the heart rate by the system and method of the current invention.
Blood pressure (BP) is the hydrostatic pressure exerted by blood on the walls of a blood vessel. The arterial blood pressure is determined by physical and physiological factors. Mean arterial pressure is the pressure in the large arteries, averaged over time. Systolic and diastolic arterial pressures are then considered as the upper and lower limits of periodic oscillations about this mean pressure. The pressure of the blood in arteries and arterioles reaches a peak, called systolic pressure, with each contraction of the heart and then gradually decreases to a minimum, the diastolic pressure before the next contraction. Blood pressure is always expressed as two figures, for example, 120/80 in healthy young adults, representing respectively the systolic and diastolic pressures in millimeters of mercury (mm Hg).
About 20% of the adult population is afflicted with hypertension, the most common single disorder seen in the office of an internist. It is a major risk factor for coronary artery disease and a common cause of heart failure, kidney failure, stroke, and blindness. For adults over 50 years of age, the diagnosis is usually based on repeated resting levels of greater than 160/95 mm Hg in adults over 50 years of age. It is more common among males than females and far more common among blacks than whites. In refractory hypertension, the BP stays at these levels despite treatment with at least two anti-hypertensive drugs for a period of time that is normally adequate to relieve the symptoms.
There is considerable evidence that the nervous system is much involved in the regulation of arterial pressure. For example, hypertension can be induced in experimental animals by transection of arterial baroceptor nerves, by lesion of the nucleus tractus solitarius (NTS). For refractory hypertension where pharmacologic therapy either is not effective, or is not tolerated because of the side effects of drugs, non-pharmacologic therapy such as afferent nerve stimulation may be another alternative for adjunct (add-on) therapy. The neuromodulation of the vagus nerve is designed to control the patient""s blood pressure, in the system and method of this invention.
One of the fundamental features of the nervous system is its ability to generate and conduct electrical impulses. These can take the form of action potentials, which is defined as a single electrical impulse passing down an axon, and is shown schematically in FIG. 2. The top portion of the figure shows conduction over mylinated axon (fiber) and the bottom portion shows conduction over nonmylinated axon (fiber). These electrical signals will travel along the nerve fibers.
The nerve impulse (or action potential) is an xe2x80x9call or nothingxe2x80x9d phenomenon. That is to say, once the threshold stimulus intensity is reached an action potential 7 will be generated. This is shown schematically in FIG. 3. The bottom portion of the figure shows a train of action potentials.
Most nerves in the human body are composed of thousands of fibers of different sizes. This is shown schematically in FIG. 4. The different sizes of nerve fibers, which carry signals to and from the brain, are designated by groups A, B, and C. The vagus nerve, for example, may have approximately 100,000 fibers of the three different types, each carrying signals. Each axon or fiber of that nerve conducts only in one direction, in normal circumstances.
In a cross section of peripheral nerve it is seen that the diameter of individual fibers vary substantially. The largest nerve fibers are approximately 20 xcexcm in diameter and are heavily myelinated (i.e., have a myelin sheath, constituting a substance largely composed of fat), whereas the smallest nerve fibers are less than 1 xcexcm in diameter and are unmyelinated. As shown in FIG. 5, when the distal part of a nerve is electrically stimulated, a compound action potential is recorded by an electrode located more proximally. A compound action potential contains several peaks or waves of activity that represent the summated response of multiple fibers having similar conduction velocities. The waves in a compound action potential represent different types of nerve fibers that are classified into corresponding functional categories as shown in the table below,
The diameters of group A and group B fibers include the thickness of the myelin sheaths. Group A is further subdivided into alpha, beta, gamma, and delta fibers in decreasing order of size. There is some overlapping of the diameters of the A, B, and C groups because physiological properties, especially in the form of the action potential, are taken into consideration when defining the groups. The smallest fibers (group C) are unmyelinated and have the slowest conduction rate, whereas the myelinated fibers of group B and group A exhibit rates of conduction that progressively increase with diameter.
Compared to unmyelinated fibers, myelinated fibers are typically larger, conduct faster, have very low stimulation thresholds, and exhibit a particular strength-duration curve or respond to a specific pulse width versus amplitude for stimulation. The A and B fibers can be stimulated with relatively narrow pulse widths, from 50 to 200 microseconds (xcexcs), for example. The A fiber conducts slightly faster than the B fiber and has a slightly lower threshold. The C fibers are very small, conduct electrical signals very slowly, and have high stimulation thresholds typically requiring a wider pulse width (300-1,000 xcexcs) and a higher amplitude for activation. Because of their very slow conduction, C fibers would not be highly responsive to rapid stimulation. Selective stimulation of only A and B fibers is readily accomplished. The requirement of a larger and wider pulse to stimulate the C fibers, however, makes selective stimulation of only C fibers, to the exclusion of the A and B fibers, virtually unachievable inasmuch as the large signal will tend to activate the A and B fibers to some extent as well.
The vagus nerve is composed of somatic and visceral afferents and efferents. Usually, nerve stimulation activates signals in both directions (bi-directionally). It is possible however, through the use of special electrodes and waveforms, to selectively stimulate a nerve in one direction only (unidirectionally). The vast majority of vagus nerve fibers are C fibers, and a majority are visceral afferents having cell bodies lying in masses or ganglia in the skull. The central projections terminate largely in the nucleus of the solitary tract, which sends fibers to various regions of the brain (e.g., the thalamus, hypothalamus and amygdala).
Vagus nerve stimulation is a means of directly affecting central function. As shown in FIG. 6, cranial nerves have both afferent pathway 19 (inward conducting nerve fibers which convey impulses toward the brain) and efferent pathway 21 (outward conducting nerve fibers which convey impulses to an effector). The vagus nerve 54 is composed of 80% afferent sensory fibers carrying information to the brain from the head, neck, thorax, and abdomen. The sensory afferent cell bodies of the vagus reside in the nodose ganglion and relay information to the nucleus tractus solitarius (NTS).
FIG. 7 shows the nerve fibers traveling through the spinothalamic tract to the brain. The afferent fibers project primarily to the nucleus of the solitary tract (shown schematically in FIG. 8) which extends throughout the length of the medulla oblongata. A small number of fibers pass directly to the spinal trigeminal nucleus and the reticular formation. As shown in FIG. 8, the nucleus of the solitary tract has widespread projection to cerebral cortex, basal forebrain, thalamus, hypothalamus, amygdala, hippocampus, dorsal raphe, and cerebellum.
In summary, neuromodulation of the vagal nerve fibers exert their influence on refractory hypertension via Afferent stimulation. And, neuromodulation of the vagal nerve fibers exert their influence on atrial fibrillation and in Inappropriate Sinus Tachycardia Syndrome via Efferent stimulation of the left and right vagus nerve respectively.
One type of non-pharmacologic, medical device therapy for cardiovascular disorders is generally directed to the use of an implantable lead and an implantable pulse generator technology or xe2x80x9ccardiac-pacemaker likexe2x80x9d technology.
U.S. Pat. No. 5,707,400 (Terry et al) is generally directed to using an implantable device like a xe2x80x9ccardiac pacemakerxe2x80x9d for treating refractory hypertension by nerve stimulation. The implanted pulse generator of this patent is programmed by an external personnel computer based programmer with a modified wand, shown in FIG. 9A. Each parameter is independently programmable. Therefore, millions of different combinations of programs are possible. In the current patent application, a limited number of programs are pre-selected. This patent neither anticipates practical problems with an inductively coupled system, nor suggests any solutions for the same.
U.S. Pat. No. 5,690,681 (Geddes et al) is directed to a closed-loop implanted vagal stimulation apparatus for control of ventricular rate during atrial fibrillation. In this patent, implanted cardiac leads, and implanted pulse generator are used for sensing signals from atrial and ventricular electrograms and an adaptive control system (controller) is used for closing the loop for output stimulation to the vagus nerve. The communication to the fully implanted system of this patent is via an external programmer. In the current patent application, the patient acts as the feedback loop.
U.S. Pat. No. 5,916,239 (Geddes et al) is directed to apparatus and method for automatically and continuously adjusting the frequency of nerve stimulator as a function of signals obtained via atrial and ventricular electrograms.
U.S. Pat. No. 5,700,282 (Zabara) is directed to simultaneously stimulating vagus efferents and cardiac sympathetic nerve efferents. The rationale being to employ the brain""s natural mechanisms for heart rhythm control.
U.S. Pat. No. 5,522,854 (Ideker et al) is generally directed to monitoring parasympathetic and sympathetic nerve activity and stimulating the afferent nerves with an implanted device, with the goal of preventing arryhthmias.
U.S. Pat. No. 5,199,428 (Obel et al) is directed to an implantable electrical nerve stimulator/pacemaker for decreasing cardiac workload for myocardial ischemia. The methodology involves stimulating the carotid sinus nerves or the stellate gantglion.
U.S. Pat. No. 5,330,507 (Schwartz) is generally directed to stimulating right or left vagus nerve with an implanted device which is an extension of a dual chamber cardiac pacemaker. The system is shown in FIG. 9B.
U.S. Pat. No. 3,796,221 (Hagfors) is directed to controlling the amplitude, duration and frequency of electrical stimulation applied from an externally located transmitter to an implanted receiver by inductively coupling. Electrical circuitry is schematically illustrated for compensating for the variability in the amplitude of the electrical signal available to the receiver because of the shifting of the relative positions of the transmitter-receiver pair. By highlighting the difficulty of delivering consistent pulses, this patent points away from applications such as the current application, where consistent therapy needs to be continuously sustained over a prolonged period of time. The methodology disclosed is focused on circuitry within the receiver, which would not be sufficient when the transmitting coil and receiving coil assume significantly different orientation, which is likely in the current application. The present invention discloses a novel approach for this problem.
U.S. Pat. Nos. 4,702,254, 4,867,164 and 5,025,807 (Zabara) generally disclose animal research and experimentation related to epilepsy and the like and are directed to stimulating the vagas nerve by using xe2x80x9cpacemaker-likexe2x80x9d technology, such as an implantable pulse generator. The pacemaker technology concept consists of a stimulating lead connected to a pulse generator (containing the circuitry and DC power source) implanted subcutaneously or submuscularly, somewhere in the pectoral or axillary region, and programming with an external personal computer (PC) based programmer. Once the pulse generator is programmed for the patient, the fully functional circuitry and power source are fully implanted within the patient""s body. In such a system, when the battery is depleted, a surgical procedure is required to disconnect and replace the entire pulse generator (circuitry and power lo source). These patents neither anticipate practical problems of an inductively coupled system, nor suggest solutions to the same for an inductively coupled system for neuromodulation therapy.
U.S. Pat. No. 5,304,206 (Baker, Jr. et al) is directed to activation techniques for implanted medical stimulators. The system uses either a magnet to activate the reed switch in the device, or tapping which acts through the piezoelectric sensor mounted on the case of the implanted device, or a combination of magnet use and tapping sequence.
U.S. Pat. No. 4,573,481 (Bullara) is directed to an implantable helical electrode assembly configured to fit around a nerve. The individual flexible ribbon electrodes are each partially embedded in a portion of the peripheral surface of a helically formed dielectric support matrix.
U.S. Pat. No. 3,760,812 (Timm et al.) discloses nerve stimulation electrodes that include a pair of parallel spaced apart helically wound conductors maintained in this configuration.
U.S. Pat. No. 4,979,511 (Terry) discloses a flexible, helical electrode structure with an improved connector for attaching the lead wires to the nerve bundle to minimize damage.
Apparatus and method for neuromodulation, of the current application has several advantages over the prior art implantable pulse generators. The external stimulator described here can be manufactured at a fraction of the cost of an implantable pulse generator. The stimulation therapy can be freely applied without consideration of battery depletion, and surgical replacement of the pulse generator is avoided. The programming is much simpler, and can be adjusted by the patient within certain limits for patient comfort. And, the implanted hardware is much smaller.
The system and method of the current invention also overcomes many of the disadvantages of the prior art by simplifying the implant and taking the programmability into the external stimulator. Further, the programmability of the external stimulator can be controlled remotely, via the wireless medium, as described in a co-pending application. The system and method of this invention uses the patient as his own feedback loop. Once the therapy is prescribed by the physician, the patient can receive the therapy as needed based on symptoms, and the patient can adjust the stimulation within prescribed limits for his/her own comfort.
The stimulation is to the right vagus nerve for controlling Inappropriate Sinus Tachycardia, and to the left vagus nerve for adjunct (add-on) treatment of atrial fibrillation and refractory hypertension.
The system consists of an implantable lead-receiver containing passive circuitry, electrodes, and a coil for coupling to the external stimulator. The external stimulator, which may be worn on a belt or carried in a pocket, contains electronic circuitry, power source, predetermined programs, and primary coil. The external primary coil and subcutaneous secondary coil are inductively coupled. The patient may selectively activate stimulation corresponding to symptoms, or leave the stimulation on according to predetermined program.
In one aspect of the invention, the pulse generator contains a limited number of predetermined programs packaged into the stimulator, which can be accessed directly without a programmer. The limited number of programs can be any number of programs even as many as 100 programs, and such a number is considered within the scope of this invention. For patient convenience, less than 20 programs are currently incorporated.
In another feature of the invention, the system provides for proximity sensing means between the primary (external) and secondary (implanted) coils. Utilizing current technology, the physical size of the implantable lead-receiver has become relatively small. However, it is essential that the primary (external) and secondary (implanted) coils be positioned appropriately with respect to each other. The sensor technology incorporated in the present invention aids in the optimal placement of the external coil relative to a previously implanted subcutaneous coil. This is accomplished through a combination of external and implantable or internal components.
In another feature of the invention, the external stimulator has predetermined programs built into the stimulator, as well as, a manual xe2x80x9conxe2x80x9d and xe2x80x9coffxe2x80x9d button. Each of these programs has a unique combination of pulse amplitude, pulse width, frequency of stimulation, on-time and off-time. After the therapy has been initiated by the physician, the patient has a certain amount of flexibility in adjusting the intensity of the therapy (level of stimulation). The patient has the flexibility to decrease (or increase) the level of stimulation (within limits). The manual xe2x80x9conxe2x80x9d button gives the patient flexibility to immediately start the stimulating pattern at any time. Of the pre-determined programs, patients do not have access to at least one of the programs, which can be activated only by the physician, or an appropriate person.